The American Academy of Pediatrics and the American Academy of Clinical Endocrinology define short stature based on height as more than two standard deviations below the average population height. A child with short stature is shorter than 97.5% of children of a similar age and gender and typically attains final adult heights of no more than approximately 5′4″ for boys and 4′11″ for girls. It is estimated that 380,000 children in the U.S. with short statue are referred to pediatric endocrinologists for evaluation.
Children with short stature who are referred for evaluation and possible treatment continue to pose a dilemma for specialists despite decades of dedicated research. For patients with no demonstrable cause for their growth failure, a workup usually ensues which first seeks to differentiate between normal variation, in which the child should reach an adult height concordant with that of his family, and pathologic conditions. In cases of marked short stature, in which the predicted adult height is also low, it often becomes necessary to test the status of the growth hormone (GH)-insulin-like growth factor (IGF) axis.
Patients with abnormalities in the GH-IGF axis have a number of possible etiologies. They can present with GH deficiency (GHD), at times attributable to congenital or acquired central nervous system (CNS) lesions affecting the hypothalamus or pituitary, which is almost invariably accompanied by low IGF-1 levels in children. Alternatively, they can present “primary IGF deficiency” associated with low IGF-1 levels in the face of seemingly normal GH secretion. Because IGF-1 is an essential mediator of GH's statural effects, primary IGF deficiency can have similar clinical outcomes to GH deficiency. Such cases of primary IGF deficiency, in otherwise healthy and well-nourished patients, are likely to be caused by a defect somewhere in the GH-IGF axis downstream from the secretion of GH. This type of GH insensitivity is as yet unexplained in most cases, although it has been associated with mutations affecting the extra-cellular domain of the GH receptor in 1-5% of idiopathic short stature (ISS) children and adults, with mutations in Stat5b, with mutations in the acid labile subunit (ALS), or with mutations or polymorphisms in the IGF-1 gene itself.
GH deficiency is well recognized as a disease requiring replacement therapy with GH for short stature and in adults for body composition, bone density, cardiac function and for well being. By contrast, low IGF levels, in the presence of normal GH secretion, has been previously usually associated only with a rare disease, recognized as Laron syndrome or growth hormone insensitivity syndrome (GHIS).
Most patients with Laron syndrome or GHIS lack growth hormone receptor binding activity and have absent or very low GH-binding protein (GHBP) activity in blood. Such patients have a mean height standard deviation score (SDS) of about −5 to −6, are resistant to GH treatment, and have increased serum concentrations of GH and low serum concentrations of insulin-like growth factor (IGF-1). As children they show a statural growth response to treatment with IGF-1.
The disease of short stature due to partial GH receptor defects was traditionally seen as primarily a disease characterized by a low GHBP level rather than a low IGF-1 level, with IGF-1 levels being only at the low end of the normal range. Specifically, the patient is defined as having a height of at least about 2 standard deviations or more below the normal mean for a corresponding age and gender (at least −2.0 SD below the mean), a serum level of high-affinity growth hormone binding protein that is at least 2 standard deviations below normal mean levels, a serum level of IGF-1 that is below normal mean levels, and a serum level of growth hormone that is at least normal.
The importance of this classification of the various factors affecting short stature is shown in the relative numbers of patients who are: 1) IGF-1 deficient and GH deficient and 2) IGF-1 deficient and GH sufficient. Current literature would predict that many more children and adults would be IGF-1 deficient due to GH deficiency than would be IGF-1 deficient and GH sufficient.
Unlike GH deficiency (GHD), IGF-1 deficiency (IGFD) has not been recognized or appreciated as a disease with endocrine origins and in need of replacement therapy. Thus, there remains a need in the art for methods of treatment of IGF-1 deficient children and adults who do not have Laron syndrome or partial growth hormone insensitivity syndrome.
The present invention addresses these needs.
Literature
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